Human immunodeficiency virus type 1 (HIV-1) infection remains a major global health problem due to the emergence of drug-resistant strains. Thus, there is an ongoing need for new therapeutics for the long-term management of HIV infection and for acute HIV-1 infection due to drug-resistant strains. HIV-1 protease inhibitors (PIs) have proven to be effective additions to existing antiretroviral regimens. However, despite the success of these agents, the emergence of mutants conferring multidrug resistance (MDR) remains a critical problem. Darunavir is a next-generation nonpeptide PI that exhibits potent antiviral activity with low toxicity in vitro and in vivo. The agent retains activity against resistant strains and has low liability for the development of resistance. Darunavir was approved by the FDA under the name PREZISTA™, and is administered in combination with a low-dose of ritonavir and other active anti-HIV agents.
The first synthesis of darunavir was described in A. K. Ghosh et al. Bioorganic & Medicinal Chemistry Letters 8 (1998) 687-690, which is herein incorporated by reference. The azido epoxide was reacted with isobutylamine in 2-propanol at 80° C. for 12 h to afford azidoalcohol. Treatment of the azidoalcohol with p-nitrobenzenesulfonyl chloride in the presence of aqueous NaHCO3, provided the corresponding azide, which was hydrogenated over 10% Pd—C in ethyl acetate to afford the amine (yield of 75-78%). This amine was transformed to darunavir (I) upon reaction with hexahydrofuro[2,3-b]furan-3-yl derivative in methylene chloride in the presence of 3 equiv of triethylamine at 23° C. for 12 h with overall yield of 60-65% according to the following scheme:

The same method is described in WO 99/067254.
Azidoepoxide is a hazard compound, which is not commercially available. Because of this, different approaches were proposed to substitute this compound with more readily available analogs. For example PCT patent applications WO 2005/063770, WO 2008/132154 disclose:                (i) amidation of (1-oxiranyl-2 phenyl-ethyl)-carbamic acid tert-butyl ester with isopropylamine according to the following scheme:        
                (ii) introducing a p-nitrophenylsulfonyl group in the resultant compound of step (i) according to the following scheme:        
                (iii) reducing the nitro moiety of the resultant compound of step (ii) according to the following scheme:        
                (iv) deprotecting the resultant compound of step (iii) according to the following scheme:        
                (v) Coupling the resultant compound of step (iv) with a (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivate, to form compound of formula (I) according to the following scheme:        

Although this process is more technological than the above described process [WO 99/067254], its overall yield is still moderate (50-55%). The moderate yield can be attributed to the multistage process leading to an overall unsatisfactory yield.
Consequently, there is a long-felt need for a process for the preparation of darunavir which not only overcomes the problems in the prior art processes as mentioned above, but is also safe, cost effective, and industrially feasible.
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is a precursor of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivates and is a key intermediate for the preparation of darunavir. (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is commercially available and may be prepared in several ways described in the literature, for example in WO 99/67254, WO 2002/060905, US 2004/127727, WO 2005/095410, WO 2003/024974, WO 2003/022853, WO 2004/033462, US 2006/148865, WO 2007/126812, US 2004/0162340 (U.S. Pat. No. 6,867,321), US 2005/256322, WO 2006/132390 (corresponding to EP 1889826), WO 2008/034598, WO 2008/055970, and Ghosh et al, J. Org. Chem. 69 (2004) 7822-7829. A common feature of some prior art processes for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is the use, at different stages of the process, of protecting groups that are acid-sensitive, and therefore removed under acidic conditions. Such acidic conditions are a prerequisite of the cyclization process forming the furanol ring. Examples of protecting groups used in the synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol include benzyl ether protecting groups, alkyl ether protective groups and silyl protecting groups.
A major disadvantage of the synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol according to the available protocols is that the desired compound is initially obtained in the form of a diastereomer racemic mixture of hexahydrofuro[2,3-b]furan-3-ols. Optical resolution methods are generally inefficient and expensive. Examples include (i) optical resolution carried out by enzymes, this reaction is inefficient since only one of the resulting enantiomers is used for the production of an intended substance, while the other enantiomer is discarded; (ii) using an optically active form as a raw material, this option is non-economical as optically active compounds are expensive; (iii) conversion of the racemic mixture into the corresponding acetate followed by enzymatic hydrolysis; and (iv) oxidizing the racemic mixture followed by a reducing step. Another clear disadvantage of the available procedures is the simultaneous deprotection (intermolecular reaction) and ring closure processes (intramolecular reaction) which take place under acidic conditions and result in reduced product yields.
Thus, there is an unmet need for a process for the synthesis of an optically active (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, which is efficient and inexpensive.